FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death

Xander H T Wehrens, Stephan E. Lehnart, Fannie Huang, John A. Vest, Steven R. Reiken, Peter J. Mohler, Jie Sun, Silvia Guatimosim, Long Sheng Song, Nora Rosemblit, Jeanine M. D'Armiento, Carlo Napolitano, Mirella Memmi, Silvia G. Priori, W. J. Lederer, Andrew R. Marks

Research output: Contribution to journalArticlepeer-review

Abstract

Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca2+ release and cardiac contractility. FKBP12.6-/- mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.

Original languageEnglish
Pages (from-to)829-840
Number of pages12
JournalCell
Volume113
Issue number7
DOIs
Publication statusPublished - Jun 27 2003

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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